Polymerization of sickle hemoglobin is determined by oxygen saturation, hemoglobin concentration and hemoglobin composition. Within the erythrocyte, hemoglobin polymerization can lead to abnormal rheology. A detailed analysis and understanding of the effect of intracellular polymerization on disease manifestation will clarify the cellular basis of disease in the sickle syndromes. Defect in urine concentrating ability is a frequent finding in individuals with sickle cell trait. The mechanism is unclear, but may result from intracellular polymerization of sickle hemoglobin in erythrocytes, leading to microvascular occusion in the vasa recta of the renal medulla. If such is the case, the severity of the concentrating defect should be determined by the percentage of sickle hemoglobin present in erythrocytes. To test this hypothesis, urinary concentrating ability was examined following overnight water deprivation and intranasal dDAVP in 27 individuals with sickle trait who had a normal alpha-globin genotype (aa/aa), or were either heterozygous (-a/aa), or homozygous (-a/-a) for gene deletion alpha thalassemia, since alpha-thalassemia modulates the sickle hemoglobin concentration in sickle trait. The urinary concentrating ability was less in the aa/aa genotype than in the -a/aa or -a/-a genotypes. Following dDAVP, the urine osmolality was greater in patients with the -a/-a genotype than the -a/a genotype (822 vs 672 mOsm/kg H20); patients with the -a/aa genotype had greater concentrating ability than individuals with a normal a-globin gene arrangement. A linear correlation also existed for urine concentrating ability and polymerization tendencies calculated for an oxygen saturation of 0.4. We conclude that the severity of hyposthenuria in sickle trait in heterogenous. It is determined by the amount of sickle hemoglobin polymer that in turn is dependent upon the percent of sickle hemoglobin, which is itself related to the a-globin genotype. Recently, we have initiated studies to examine the effect of fetal hemoglobin on the solubility of deoxyhemoglobin S under physiological conditions and of the effect of polymer formation on the rheological properties of the sickle erythrocyte. Both of these analyses will further understand the relationship between polymer formation and disease severity.